Opioids have been widely used as narcotic medications that activate opioid receptors located in the central nervous system to relieve pain in patient therapy. Opioids, however, also react with receptors in the peripheral nervous system, resulting in side effects, including constipation, nausea, vomiting, urinary retention and severe itching. Most notable are the effects in the gastrointestinal tract (GI) where opioids inhibit gastric emptying and propulsive motor activity of the intestine, thereby decreasing the rate of intestinal transit, which can produce constipation. The effectiveness of opioids for pain therapy is often limited due to resultant side effects, which can be debilitating and often cause patients to cease use of opioid analgesics.
Endogenous opioid compounds and receptors may also affect activity of the gastrointestinal (GI) tract and may be involved in normal regulation of intestinal motility and mucosal transport of fluids in both animals and man. (Koch, T. R, et al., Digestive Diseases and Sciences 1991, 36, 712-728; Schuller, A. G. P., et al., Society of Neuroscience Abstracts 1998, 24, 524, Reisine, T., and Pasternak, G., Goodman & Gilman's The Pharmacological Basis of Therapeutics Ninth Edition 1996, 521-555 and Bagnol, D., et al., Regul. Pept. 1993, 47, 259-273). Thus, an abnormal physiological level of endogenous compounds and/or receptor activity may lead to bowel dysfunction.
Compounds that bind to opioid receptors (mu-, kappa- and delta-receptors) have been found useful in the treatment of diseases modulated by opioid receptors, for example, as discussed above, functional gastrointestinal disorders, including, but not limited to irritable bowel syndrome, constipation, ileus, nausea, vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opioid receptors have also been indicated in the treatment of additional conditions, including eating disorders, opioid overdoses, depression, anxiety, schizophrenia, addiction and dependence disorders (e.g., smoking, alcohol, narcotic, behavioral addictions and dependencies), sexual dysfunction, shock, stroke, spinal damage and head trauma, among others.
Opioid antagonists such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing undesirable peripheral effects of opioids. However, these agents act not only on peripheral opioid receptors, but also on central nervous system sites, so that they sometimes reverse the beneficial analgesic effects of opioids, or cause symptoms of opioid withdrawal. Preferable approaches for use in controlling opioid-induced side effects in patients include use of peripheral opioid antagonist compounds that do not readily cross the blood-brain barrier. For example, the peripheral μ opioid antagonist compound methylnaltrexone and related compounds have been disclosed for use in curbing opioid-induced side effects in patients (e.g., constipation, pruritus, nausea, and/or vomiting). See, e.g., U.S. Pat. Nos. 5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan, C.-S. et al. Drug and Alcohol Dependence 1998, 52, 161. The S-methylnaltrexone compound has been isolated and found to be a peripheral μ opioid agonist, while the R-methylnaltrexone compound retains antagonist activity. See, e.g., U.S. patent application Ser. Nos. 11/441,452, filed May 25, 2006, published WO2006/127898, and 11/441,395 filed May 25, 2006, published WO2006/127899. Methylnaltrexone is commercially available. For example, methylnaltrexone is available in a powder form from Mallinckrodt Pharmaceuticals, St. Louis, Mo., provided as a white crystalline powder freely soluble in water.
Thus, identification of new therapeutic agents and methods for the treatment of side effects and/or disorders mediated by opioid receptor actions are useful for providing alternatives and/or improvements to currently available therapies.